ENDOTHELIAL AT(1)-MEDIATED RELEASE OF NITRIC-OXIDE DECREASES ANGIOTENSIN-II CONTRACTIONS IN RAT CAROTID-ARTERY

The purpose of this study was to examine whether angiotensin II (Ang II) stimulates the release of endothelium-derived nitric oxide, which then impairs the contractions of vascular smooth muscle caused by the peptide, and to determine the receptor subtypes mediating these responses. Experiments were performed on isolated rings of rat carotid artery either incubated in the presence of phosphodiesterase inhibitor for the measurement of intracellular levels of cGMP or suspended in organ chambers for recording of changes in isometric force. Ang II (10(-7) mol/L) caused a twofold increase in intracellular cGMP level in preparations with but not in those without endothelium. The presence of endothelium impaired the contractions evoked by the peptide and caused approximately 50% inhibition of the maximal response to Ang II (3x10(-8) mol/L); pD(2) values for Ang II were 8.9+/-0.1 and 9.6+/-0.2 in rings with and without endothelium, respectively. Tn rings with endothelium the contractions to Ang II were augmented by nitro-L-arginine (an inhibitor of nitric oxide synthase) but not indomethacin (an inhibitor of cyclooxygenase), to reach a response comparable to that of preparations without endothelium. In rings without endothelium losartan (a preferential angiotensin type 1 receptor antagonist) displayed competitive antagonism toward Ang II (pA(2)=9.5); PD 123319 (a preferential angiotensin type 2 receptor antagonist; up to 10(-7) mol/L) did not affect the response to the peptide. Losartan (3x10(-9) mol/L) but not PD 123319 (10(-7) mol/L) impaired the endothelium-dependent component of the response to the peptide. These results suggest that in the rat carotid artery stimulation of an Ang II type 1 receptor causes the release of nitric oxide, which in turn inhibits the contractions to Ang II also mediated by type 1 receptors.